tbuckley/cabot-search huggingface dataset:
EXTH-69. ASTROCYTOMA CELLS HARBORING MUTANT IDH1 ARE UNIQUELY SENSITIVE TO INHIBITION OF OXIDATIVE PHOSPHORYLATION
Authors: Anagha Gurjar, Howard Colman, Sheri Holmen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Diffuse gliomas are the most common primary brain tumor in adults, affecting ~20,000 people in the United States each year. Current treatment modalities, which include surgery, radiation, and chemotherapy, are relatively ineffective against these tumors and the prognosis is poor. Although most cancer cells rely on glycolysis to generate ATP, IDH1 mutant gliomas show enhanced dependence on oxidative phosphorylation. Thus, we evaluated the effect of IACS-010759, a potent and selective inhibitor of complex I that interferes with cellular respiration, in multiple patient-derived glioma cells. METHODS In the present study, we used six different patient-derived glioma cell cultures including four that are IDH1 wild type (wt) (GSC 20, GSC 23, LN 18 and SF 268) and two that are IDH1R132H mutant (BT142 &amp; 21238-IDH1R132H). All cells were cultured as neurospheres to maintain glioma stem cell (GSC) culture conditions. The toxicity of IACS-010759 was also evaluated in immortal non-transformed mouse astrocytes. Neurospheres and astrocytes were treated with IACS-010759 (0.1 µM-100 µM) and cell viability was evaluated after 72 hours using CellTiter-Glo. RESULTS Inhibition of oxidative phosphorylation significantly reduced cell proliferation in all glioma cells evaluated. The IC50 of IACS-010759 ranged from 0.7 nM-100 µM but was lowest in IDH1R132H astrocytoma cells, supporting the hypothesis that IDH1 mutant astrocytoma cells have enhanced dependence on oxidative phosphorylation. Importantly, immortal, non-transformed astrocytes were relatively resistant to IACS-010759 suggesting that this strategy may have an effective therapeutic window in this disease. CONCLUSION In summary, IACS-010759-induced inhibition of oxidative phosphorylation elicited pronounced anti-neoplastic responses in vitro, especially in astrocytomas expressing mutant IDH1. IACS-010759 may be a promising therapy for both IDH1 wt and mutant gliomas, and we are currently evaluating the efficacy of this strategy in glioma mouse models.
CSIG-26. PROTEIN KINASE B (PKB/AKT) PROTECTS IDH-MUTATED GLIOMA FROM FERROPTOSIS VIA NRF2
Authors: Yang Liu, Fengchao Lang, Chunzhang Yang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Mutations of the isocitrate dehydrogenase (IDH) gene are highly prevalent in WHO II/III glioma. IDH-mutated glioma frequently exhibits strong molecular signatures of PI3K/AKT/mTOR signaling, whereas the precise roles of this oncogenic pathway in IDH-mutated glioma remain elusive. METHODS In this study, we performed unbiased RNA sequencing and gene set enrichment analysis (GSEA) to investigate the relevant molecular pathways governed by the Phosphoinositide 3-kinase (PI3K)/AKT in IDH-mutated cancer cells. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione de novo synthesis were further analyzed through biochemistry assays. Moreover, the role of AKT in glioma disease outcomes was evaluated in a preclinical animal model bearing IDH-mutated orthoptic intracranial xenograft. RESULTS RNA sequencing and GSEA analysis indicated that the AKT pathway significantly correlated with Nrf2-guided gene expression and ferroptosis-related pathways. Mechanistically, AKT activation compromised the phosphorylation of Nrf2 at its SDS domain, which is a critical post-translational modification that determines Nrf2 degradation through an E3 ligase β-transducin repeat-containing protein (β-TrCP). Thus, the activation of the AKT pathway limited the proteolysis of Nrf2 and a remarkably enhanced Nrf2 transcriptional activity, which enables cytoprotective pathways such as antioxidant, tumor microenvironment remodeling, and ferroptosis protection. Moreover, a combination of AKT inhibitor ipatasertib with genotoxic agent temozolomide resulted in potent synthetic lethality in IDH-mutated cancer cells, highlighted with enhanced ferroptotic cell death. Further, the AKT inhibitor and TMZ combination regimen improved disease outcomes in a preclinical animal model with IDH-mutated orthotopic intracranial xenograft, with significantly prolonged overall survival. CONCLUSION Overall, our findings revealed an uncharted oncogenic mechanism in IDH-mutated glioma, highlighted with AKT/Nrf2-guided cytoprotective pathway. Our study also provides critical preclinical evidence for a synthetic lethality approach for IDH mutated cancers.
IMMU-23. ELIMINATING MONOCYTE CHEMOATTRACTION INVOKES COMPENSATORY NEUTROPHIL INFLUX AND PRONEURAL TO MESENCHYMAL TRANSITION IN GLIOBLASTOMA
Authors: Zhihong Chen, Nishant Soni, Gonzalo Pinero, Bruno Giotti, Devon Eddins, Katherine Lindblad, James Ross, Nadejda Tsankova, David Gutmann, Sergio Lira, Amaia Lujambio, Eliver Ghosn, Alexander Tsankov, Dolores Hambardzumyan
Journal: Neuro-Oncology (2022)

Abstract Myeloid cells comprise the majority of immune cells in tumors, where their content and composition is determined by tumor type and driver mutation. While these cells are essential for shaping the tumor microenvironment, promoting tumor growth, and contributing to therapeutic resistance, targeting tumor-associated myeloid cells, including bone-marrow-derived monocytes and neutrophils, has not been successful in the clinics. Monocyte chemoattractant protein (MCP) family, comprising of Ccl2, Ccl7, Ccl8, Ccl12, are essential for monocytes trafficking to the tumor sites. To eliminate monocyte recruitment, we leveraged CRISPR/Cas-9 based gene editing tool to generate a mouse strain that is devoid of all MCP genes, which we termed quadruple MCP knockout (qMCP-/-). Using these mice in combination with genetically engineered mouse models (GEMM) of glioblastoma (GBM), we abolished tumor monocyte infiltration. Due to the functional redundancy of MCP family members, we show that targeting individual MCP genes leads to compensation by other MCPs. In contrast, when all MCPs are genetically deleted and monocyte recruitment is abolished, neutrophil infiltration ensues. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Remarkably, pharmacologic or genetic interventions that suppress both monocytes and neutrophil infiltration improve the survival of GBM-bearing mice. Taken together, our findings establish that specific subsets of myeloid cells can influence the dynamism of tumor microenvironment, and they emphasize the importance of targeting both monocytes and neutrophils simultaneously for effective GBM immunotherapy.
DDEL-03. ASSESSING THE DEPTH OF DRUG PENETRATION INTO BRAIN PARENCHYMA FROM LOCAL DRUG DELIVERY SYSTEMS IN AN ORTHOTOPIC HIGH GRADE GLIOMA ALLOGRAFT USING ORBITRAP-SECONDARY ION MASS SPECTROMETRY
Authors: Cara Moloney, Phoebe McCrorie, Chiara Bastianchich, Bernard Ucakar, Cameron Alexander, Maria Marlow, Véronique Préat, Ruman Rahman
Journal: Neuro-Oncology (2022)

Abstract Local intracranial drug delivery for high-grade glioma has been developed over the last two decades with chemotherapeutic agents administered immediately adjuvant to neurosurgery to overcome poor blood brain barrier permeability. In addition to this, the incorporation of nanoparticles (NPs) into local drug delivery systems (DDS) can result in increased penetration of chemotherapeutics through brain parenchyma, transporting the drug further from the administration site than by drug molecule diffusion alone.Here we adopted two model local DDS containing NPs to compare the depth of penetration through brain parenchyma. Approach one consisted of a thermosensitive in situ assembling polymer matrix loaded with polymer-doxorubicin conjugated NPs which can line the resection cavity walls, while approach two consisted of drug-loaded (etoposide and olaparib) poly(lactic acid)-poly(ethylene glycol) polymeric NPs held within a bioadhesive pectin hydrogel and delivered via a spray device.We assessed the efficacy of both DDS at preventing recurrence of high-grade glioma in an orthotopic rat 9L gliosarcoma model following surgical resection. In addition to monitoring long-term survival, the effect of each DDS was measured histologically by H&amp;E and by caspase-1 (inflammatory response) and ki67 (cell proliferation) immunostaining staining. Depth of drug penetration was evaluated on post-sacrificial sections using Orbitrap-Secondary Ion Mass Spectroscopy (OrbiSIMS) and fluorescent microscopy. In vivo data suggests that the delivery mechanism of the NPs affects the efficacy of the DDS, whereby long-term survival was observed in rats treated with the sprayed olaparib/etoposide NP formulation, relative to rats where olaparib/etoposide was simply pipetted into the resection cavity. OrbiSIMS confirmed the presence of doxorubicin, olaparib and etoposide in brain tissue. Our work encourages consideration of mass spectrometry modalities to complement in vivo efficacy studies, as an analytical tool to assess brain distribution of systemically administered drugs, or localised brain penetration of drugs released biomaterial-based DDS.
CNSC-15. DECIPHERING RAMAN-SPECTRAL TISSUE HETEROGENEITY IN GLIOBLASTOMA
Authors: Karoline Klein, Gilbert Georg Klamminger, Laurent Mombaerts, Finn Jelke, Giulia Mirizzi, Redouane Slimani, Andreas Husch, Michel Mittelbronn, Frank Hertel, Felix Kleine Borgmann
Journal: Neuro-Oncology (2022)

Abstract Raman Spectroscopy is able to provide a fast identification method for healthy and pathological tissues without the need for sample preparation. This makes it highly interesting for intraoperative use in identifying tumor types and borders. However, the capability of a machine-learning classifier to recognize known tissues based on Raman spectra relies on a solid ground truth that is usually provided by measuring small tissue samples first and analyzing the sample later by histopathology. This approach is limited in very closely interspersed tissues that cannot be identified macroscopically, such as glioblastoma where vital tumor tissue, necrosis and peritumoral tissue with characteristic changes to healthy brain tissue are tightly arranged. These areas have been shown to be distinct in their spectral properties, which makes tumor border identification aided by Raman Spectroscopy challenging. As infiltrative tumors leaving no tumor-cell-free brain tissue, borders need to be defined on a clinical scale, where extensive resection must be weighed against retaining functional brain tissue. For this, spectral analysis beyond tumor identification is necessary. In a computational approach we use methods of unsupervised learning and K-means Clustering to investigate heterogeneity within glioblastomas in the native state in order to reduce the complexity of this tumor type. Thereby, it was possible to extract spectra of necrotic tumor areas and to calculate a prediction probability for necrotic tissue within glioblastomas. Several clusters with spectral similarity to each other could be identified, which might represent the different areas of a glioblastoma. Two of these clusters were identified as probable grey and white matter, respectively, by comparison with autopsy tissue. In addition, this assignment independently confirmed the prediction of the classifier as non-necrotic tissue. Deciphering the spectral heterogeneity of glioblastoma in this way may be a great advantage for the surgeon to identify tumor borders and assist in resection control.
CTNI-01. EFFECT OF PRE-OPERATIVE STEREOTACTIC RADIOSURGERY ON BRAIN METASTASIS: ANALYSIS OF DNA AND RNA GENOMIC PROFILES FROM PHASE-II CLINICAL TRIAL NCT03398694
Authors: Jack Shireman, Wei Huff, Gina Monaco, Namita Agrawal, Gordon Watson, Mahua Dey
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising. Treatment varies based on presentation, however, for patients with &amp;lt; 4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence, and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1-4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor. METHODS Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. RESULTS/CONCLUSIONS Our initial data analyses show that pre-treatment with SRS results in significant genomic changes at DNA and RNA levels throughout the tumor when compared to non-radiated tumors. In matched center and peripheral samples DNA damage levels, measured by high impact mutation load, were similar indicating no evidence of radiation dose fall off effect on DNA damage. However, differing DNA damage locations and RNA expression profiles between center and matched samples are present, which may indicate unequal DNA repair processes between the center and periphery of tumors. Furthermore, global DNA mutation and RNA expression profiles differed significantly between the metastasis of different primary cancers signaling the importance of the primary cancer location in determining viable therapeutic targets.
STEM-03. MOLECULAR PROFILING OF PRIMARY VERSUS RECURRENT GLIOBLASTOMA BRAIN TUMOR STEM CELLS UNCOVERS SIGNALING MECHANISMS THAT PROMOTE THE AGGRESSIVENESS OF RECURRENT GLIOBLASTOMA
Authors: Kyle Heemskerk, Xiaoguang Hao, Orsolya Cseh, H Artee Luchman, Samuel Weiss
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is a devastating brain cancer with a median overall survival of a mere 12-15 months. Patients receive the standard of care treatment, comprised of maximum surgical resection, ionizing radiation, and temozolomide chemotherapy, however the tumor inevitably recurs. Recurrent GBM is more invasive, difficult to resect, and treatment resistant. GBM brain tumor stem cells (BTSCs), a sub-population of stem-like tumor cells with the ability to self-renew and differentiate into a heterogeneous tumor, are thought to be at the root of recurrent disease. BTSCs isolated from primary and recurrent tumors from the same patient are rare due to fewer resections of recurrent tumors and reduced quality of recurrent tumor samples used to initiate cell lines. As a result, the process of tumor recurrence is vastly understudied in BTSCs. To further understand the process of recurrence and elucidate potential mechanisms of invasion and treatment resistance, we explored global transcriptomics in 40 primary versus 17 recurrent BTSC cultures. Additionally, we profiled changes at the chromatin level in a subset of primary versus recurrent BTSCs using ATAC sequencing. Several pathways were found to be upregulated in recurrent GBM BTSCs, including innate immune signaling at the mRNA and chromatin level, which may mediate the aggressive nature of recurrent BTSCs. Moreover, these signaling changes may be unique to the stem cell population within the tumor, as they are not observed when profiling primary versus recurrent bulk tumors. We are currently targeting these pathways genetically and pharmacologically in primary and recurrent GBM BTSCs established from the same patient and have uncovered mechanisms for treatment resistance, invasion, and recurrence. Our work investigating global signaling changes in primary versus recurrent BTSCs holds promise for uncovering new therapeutic targets or biomarkers for treatment of recurrent GBM.
SURG-12. SURGICAL INTERVENTION FOR PRIMARY B-CELL LYMPHOMA OF THE SPINE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF CLINICAL PRESENTATION, HISTOLOGICAL MARKERS, TREATMENTS, AND SURVIVAL OUTCOMES
Authors: Julian Gendreau, Neal Patel, Nolan Brown, Seung Jin Lee, Andrew Chan, Ronald Sahyouni
Journal: Neuro-Oncology (2022)

Abstract B-cell lymphoma is a potential cause of spinal cord compression that presents with nonspecific symptoms and inconsistent imaging findings. Surgical decompression is a mainstay for both diagnosis and management especially in patients with acute neurologic deficits; however, the long-term efficacy of intervention is still unclear. We perform a systematic review of the clinical symptoms, radiographic findings, and outcome after spinal decompression in B-cell lymphoma. The databases of Medline, PubMed, and the Cochrane Database of Systemic Reviews were queried for all articles reporting spinal B-cell lymphoma. Data on presenting symptoms, histological markers, treatment and survival outcomes were extracted. Bivariate and Multivariate Cox survival regression models and Kaplan-Meier curves were generated using R software survival package. In total, 57 studies were included with 72 patients diagnosed with spinal B-cell lymphoma. Mean age was 56.22 (IQR: 45.00-70.25) with 68% of patients being male and 4.2% of patients being immunocompromised. Back pain was the most common symptom (74%) with B symptoms and cauda equina symptoms present in only 6% and 29% respectively. Mean length of symptoms before presentation was 3.81 months (IQR: 0.45-3.25). The most common location was the thoracic spine (53%), with a majority of the lesions being hyperintense (28%) on T2 MRI. Surgical resection was performed in 83% of patients. Symptoms improved in 88% of patients after surgery and 80% of patients treated nonoperatively. OS at one- and five-years was 85% (95% CI: 0.749-0.953; n=72) and 66% (95% CI: 0.512-0.847; n=72), respectively. Age &amp;gt; 70 was associated with poorer OS in bivariate (HR 4.07 [95% CI: 1.328-12.46], p &amp;lt; 0.01; n=72) and multivariate analysis (HR 3.829 [95% CI: 1.158-12.662], p &amp;lt; 0.03; n=72). Primary spinal B-cell lymphoma can have a variety of presentations. Both surgery and nonoperative management may have similar improvement in symptoms. Age &amp;gt; 70 appears to confer poorer OS.
STEM-14. NEAR-INSTANT DETECTION OF GLIOMA STEM CELLS IN LIVE HUMAN GBM-TISSUE
Authors: Oscar Persson, Christina Neofytou, Lily Keane, Margret Jensdottir, Bertrand Joseph, Ola Hermanson, Shirin Ilkhanizadeh
Journal: Neuro-Oncology (2022)

Abstract Emerging research suggests that failure to target glioma stem cells (GSCs) rather than the inability to remove tumors through surgery, radiation, or chemotherapy, explains the poor survival of GBM patients. In this study, a luminescent conjugated oligothiophene (LCO), named GlioStem (p-HTMI), is used for non-invasive and non-amplified real-time detection of GSCs in live human GBM-tissue. More than 90 patient samples were stained, quantified, and analyzed by fluorescent microscopy for the presence of Gliostem-positive (GS+) cells. Approximately 30 of the samples were FACS-sorted for GS+ and GS- cells where quantification by FACS could verify microscopy results. In addition, GS+ cells were shown to express significantly higher levels of stem cell markers (CD271, CD133, PDGFRa, CD44) in FACS-experiments. Bulk RNA sequencing of 7 GBM patient samples with paired GS+ and GS- sorted cells revealed that GS+ patient samples clustered together, whereas the GS- populations did not cluster together neither with each other nor with the GS+ populations. These data suggest a distinct heterogeneity in the GS- samples and a certain level of homogeneity regarding the GS+ populations, independent of intra-patient or patient-to-patient heterogeneity. Moreover, the GS+ samples were found to express significantly higher levels of stem cell markers including SOX10, OLIG1/2, and ASCL1, compared to the GS- samples. More specifically, the GS+ samples exhibited significantly higher expression of 35 genes associated with stemness compared to the GS- samples, with most markers being associated with pre-oligodendrocyte precursor cells (pre-OPCs) and pro-neural subtypes. Our results suggest that GlioStem is a versatile tool for near-instant and selective detection of GSCs in live tumor tissue. Detecting and eliminating these cells during tumor resection may therefore be an important aim in efficiently preventing tumor regrowth and would mean a crucial step towards increased patient survival.
INNV-27. SAFETY OF DIRECT ORAL ANTICOAGULANTS AS COMPARED TO LOW MOLECULAR WEIGHT HEPARIN IN TREATING VENOUS THROMBOEMBOLISM IN PATIENTS WITH PRIMARY BRAIN TUMORS AND BRAIN METASTASES
Authors: Assad Ali, Nirja Shah, Raphael Bastianon Santiago, Mauricio Mandel, Michal Obrzut, Hamid Borghei-Razavi, Badih Adada, Surabhi Ranjan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Patients with brain tumors (PBTs) have a 20 to 30% incidence of venous thromboembolism (VTE) Recently, new direct oral anticoagulants (DOACs) such as rivaroxaban, apixaban, dabigatran and edoxaban, have gained popularity in treating VTE in cancer patients due to ease of administration and favorable safety profile. DOACs are also being used in treating VTE in in PBTs. While clinical trials have established the safety of DOAC use in systemic cancers, there is only limited literature on safety of DOAC in PBTs. In this review, we explore all prospective and retrospective studies to evaluate the safety of DOAC in comparison to LMWH in treating VTEs in PBTs. METHODS A search on PubMed database using keywords “Direct Oral Anticoagulant,” OR “Oral Anticoagulant,” AND “Cancer,” AND “Clinical Trial” was performed for clinical trials. Another search using keywords “Direct Oral Anticoagulants,” OR “Oral Anticoagulant,” AND “Brain Tumor,” AND “Retrospective.” was performed for retrospective studies. RESULTS Of 359 clinical trials in cancer patients, only 4 evaluating DOAC versus LMWH, included PBTs– Hokusai, Select D, ADAM VTE and EINSTEIN-DVT/PE. Four retrospective studies (Lee 2021, Carney 2019, Schwartz 2021 and Leader 2021) were identified.These four clinical trials enrolled a very limited number of PBTs (0.7, 1.5%, 2.7% and 6.8% of all patients). The risk of ICH with DOAC as compared to LMWH was low in Hokusai trial (OR = 0.93; CI=0.14-5.9) and uninformative in other 3 trials (0 episodes of ICH in either/both groups). All four retrospective studies showed no increase in incidence of ICH in the DOAC versus LMWH group in PBTs. CONCLUSION In the small number of prospective and retrospective studies which have evaluated the safety of DOAC in comparison to LMWH in brain tumors, the use of DOAC appears to be safe with no increase in the risk of ICH over LMWH.